A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH.

Arcuate nucleus (ARC) neurons sense the fed or fasted state and regulate hunger. Agouti-related protein (AgRP) neurons in the ARC (ARC neurons) are stimulated by fasting and, once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARC) neurons are viewed as the counterpoint to ARC neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARC neurons, ARC neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARC projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVH neurons). Transmission across the ARC→PVH synapse is potentiated by the ARC neuron-derived MC4R agonist, α-melanocyte stimulating hormone (α-MSH). This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides insight into regulation of hunger and satiety.